1. Challenging cases: Which imaging technique to use and to incorporate into clinical practice Consultant Haematologist University College London Hospital & North Middlesex University Hospital Dr Neil Rabin

2. Case 1 William 54 year old male Referred with incidental finding of IgG kappa paraprotein Asymptomatic Investigations: Hb 119g/L, WBC 6.6 x10^9/L, /Platelets 289 x 10^9/L Creatinine normal Calcium normal Paraprotein 31 g/L Kappa LC 1429mg/L, Lambda LC 21 mg/L BJP negative by immunofixation Beta 2 m 3.2 mg/L Albumin 41 g/L Bone marrow 30% plasma cells FISH – loss of IgH nil else

3. Case 1: William What imaging do you organise for him?

4. Case 1: William Skeletal survey (plain x-ray) Skeletal survey (plain x-ray) and MRI spine Whole body MRI PET/CT Low dose whole body CT

5. Lancet Oncology Vol 15 Nov 2014

6. IMWG criteria for diagnosis MM MYELOMA Clonal bone marrow plasma cells ≥ 10% or biopsy proven plasmacytoma Evidence of organ damage: Hypercalcaemia (>2.75 mmol/L) Renal insufficiency: cr cl 177 umol/L Anaemia: Hb less than 2g/dL or below 100g/L Bone disease Biomarker suggestive of high risk of progression Lancet Oncology Vol 15 Nov 2014

7. IMWG criteria for diagnosis MM BONE DISEASE Osteolytic bone lesions OR osteoporosis & compression fractures attributable to clonal plasma cell disorder PET/CT (care with PET) low dose whole body CT MRI whole body or spine (modality determined by availability and resource) One or more site at least 5mm If only one osteolytic lesion + 10% clonal PC, no indication for treatment (other than RT) if no other criteria met for active myeloma = Solitary Plasmacytoma with minimal BM involvement Lancet Oncology Vol 15 Nov 2014

8. IMWG criteria for diagnosis MM SMOULDERING MYELOMA IMWG propose a number of ‘Myeloma defining biomarkers’ that accurately predict an 80% progression rate to overt CRAB positive myeloma within two years, and, when present these should confirm the diagnosis of multiple myeloma that requires treatment Myeloma defining BIOMARKERS Bone marrow plasmacytosis of ≥ 60% Serum free light chain ratio of ≥ 100 (involved FLC greater than 100) More than one focal bone lesion (CT, MRI, PET) Lancet Oncology Vol 15 Nov 2014

9. NICE guidance for diagnosis MM Imaging for people with suspected myeloma 1.3.1 Offer imaging to all people with a plasma cell disorder suspected to be myeloma. 1.3.2 Consider whole ‑ body MRI as first ‑ line imaging. 1.3.3 Consider whole ‑ body low ‑ dose CT as first ‑ line imaging if whole ‑ body MRI is unsuitable or the person declines it. 1.3.4 Only consider skeletal survey as first ‑ line imaging if whole ‑ body MRI and whole ‑ body low ‑ dose CT are unsuitable or the person declines them. 1.3.5 Do not use isotope bone scans to identify myeloma ‑ related bone disease in people with a plasma cell disorder suspected to be myeloma. NICE guidelines [NG35] Published date: February 2016

10. NICE guidance for diagnosis MM (imaging) Imaging for people with newly diagnosed myeloma 1.3.6 For people with newly diagnosed myeloma or smouldering myeloma who have not had whole ‑ body imaging with 1 of the following, consider whole ‑ body imaging to assess for myeloma ‑ related bone disease and extra ‑ medullary plasmacytomas with one of: MRI CT fluorodeoxyglucose positron emission tomography CT (FDG PET ‑ CT). NICE guidelines [NG35] Published date: February 2016

11. NICE guidance for diagnosis MM (imaging) 1.3.7 For guidance on imaging for people with suspected spinal cord compression, see the NICE guideline on MSCC. 1.3.8 Consider baseline whole ‑ body imaging with MRI or FDG PET ‑ CT for people who have non ‑ secretory myeloma or suspected or confirmed soft tissue plasmacytomas and have not already had either of these tests. NICE guidelines [NG35] Published date: February 2016

12. Case 1: William

13. Case 1 William Bone marrow – 30% Skeletal survey Normal Whole body diffusion weighted MRI No focal bone disease noted Small abnormal area noted in distal left femoral diaphysis (follow up imaging unchanged) Note elevated FLC ratio >100 Clinical decision not to treat Expectant follow up, remains well for > 2 years

14. Case 2 Susan 51 year old female Referred for investigation of mild anaemia Asymptomatic Investigations: Hb 108 g/L, WBC 3.7 x10^9/L, Platelets 280 x 10^9/L Creatinine normal Calcium normal Paraprotein 31 g/L Kappa LC 1.2 mg/L, Lambda LC 359.3 mg/L BJP 0.01g/L Beta 2 m 2.9 mg/L Albumin 4 g/L Bone marrow 10% plasma cells FISH – IgH:CCDN1

15. Case 2: Susan What imaging do you organise for her?

16. Case 2: Susan Skeletal survey (plain x-ray) Skeletal survey (plain x-ray) and MRI spine Whole body MRI PET/CT Low dose whole body CT

17. ‘Morphological’ vs ‘Functional’ imaging techniques WBXR and CT are referred to as ‘morphological’ imaging techniques assess the damage to mineralised bone induced by the tumour not the activity or viability of tumour cells. MRI and PET/CT are ‘functional’ imaging methods microcirculation within the bone marrow and the diffusion of interstitial water molecules or glucose uptake surrogate markers for tumour activity.

18. Charlotte Pawlyn et al. Blood 2015;126:1758

19. PFS according to PET-CT negativity vs PET-CT positivity before maintenance therapy p = 0.0004. Philippe Moreau et al. Blood 2015;126:395 OS according to PET-CT negativity vs PET-CT positivity before maintenance therapy p = 0.01 MRI vs PET-CT at Diagnosis and before maintenance therapy in Myeloma patients - IFM/DFCI 2009 Trial 134/700 patients VRD +/- ASCT prior to maintenance MRI (spine and pelvis) cf. PET/CT Compared at diagnosis, 3 mo., 12 mo. Diagnosis: MRI + 94.7% PET + 91% 3 months: MRI + 93%PET + 55% 12 months: MRI + 83%PET + 21%

20. Case 2: Susan Normal skeletal survey

21. Multiple focal lesions in spine and skull

22. Case 2: Susan Whole body diffusion weighted MRI Small tumour deposits noted throughout thoraco- lumbar spine Multiple deposits in the skull Lesion in scapulae and pelvis Diagnosed with (symptomatic) myeloma Treated with bortezmib based induction regimen prior to ASCT

23. Case 3 Sanjay 70 year old male Referred with plasma cell neoplasm detected in lytic lesion, right acromion Investigations: Hb 117 g/L, WBC 4.8 x10^9/L, /Platelets 106 x 10^9/L Creatinine normal Calcium normal Paraprotein - negative Kappa LC 150.9 mg/L, Lambda LC 7.4 mg/L BJP 0.01 g/L Beta 2 m 2.6 mg/L Albumin 42 g/L Bone marrow 20% plasma cells FISH – IgH:CCND1

24. Case 3 Sanjay Myeloma (symptomatic) Plasmacytoma in acromion Low level clonal plasma cells Disease elsewhere ? Skeletal survey normal MRI spine normal

25. Case 3: Sanjay wbMRI detects multi-focal disease

26. Case 3: Sanjay wbMRI demonstrates Response to treatment -Bortezomib based induction regimen -Prior to ASCT

27. Case 4 Helen 35 year old female Referred for investigation of lesions noted in distal femur and proximal femur Pain around her right knee Investigations: Hb 128g/L, WBC 5.3 x10^9/L, /Platelets 260 x 10^9/L Creatinine normal Calcium normal Paraprotein negative (immunofixation) Kappa LC 55.1 mg/L, Lambda LC 17.8 mg/L (ratio 3.1) BJP negative by immunofixation Beta 2 m 1.9 mg/L Albumin 47 g/L Bone marrow clear FISH – normal (no PC in BM biopsy)

28. Case 4: Helen What imaging do you organise for her?

29. Case 4: Helen Skeletal survey (plain films) + MRI spine Low dose whole body CT Whole body MRI PET/CT

30. Case 4: Helen Fused FDG PET-MRI

31. Case 4: Helen Fused FDG PET-MRI

32. Case 4: Helen MR/PET Lesion right tibia intensely FDG avid Lesion right medial posterior condyle (2 lesions) Lesion (2.1 cm) upper pole right kidney Biopsy renal lesion Atypical plasma cells, 138+, 56+, Kappa + Ovarian stimulation and egg harvest Diagnosed with myeloma / multiple plasmacytomas VTD x 4 (less than 50% reduction in size) VDT-PACE prior to ASCT

33. Case 4: Helen PET-MR PET-CT – resolution of FDG avid lesion

34. Case 4: Helen Right Tibial plateau SUV decrease 7 to 4.6 Right Femoral condyle SUV decrease 8 to 4.2 PET-CT

35. Case 4: Helen Functional imaging is important in those with oligo- secretory disease Choice of wbMRI or PET Needs to be quantitative, not just qualitative Responded to induction therapy Proceeded to ASCT Use PET to assess response and follow up

36. Case 5 Tom 54 year old male Referred right chest wall mass, arising from 8 th and 9 th rib Biopsy = plasmacytoma Investigations: Hb 112 g/L, WBC 5.8 x10^9/L, /Platelets 224 x 10^9/L Creatinine normal Calcium normal Paraprotein - none Kappa LC 4156 mg/L, Lambda LC 5.8 mg/L BJP 0.81 g/L Beta 2 m 1.5 mg/L Albumin 46 g/L Bone marrow 10% plasma cells FISH – normal

37. Case 5: Tom Kappa LC = 4156 mg/L 8 th rib 3.2 x 2.2 cm (SUV 4.4) 9 th rib 3.7 x 1.9 cm (SUV 4.2) Kappa LC = 32 mg/L 8 th rib 3.2 x 1.7 cm (SUV 2.9) 9 th rib 3.9 x 1.9 cm (SUV 2.9) PET-CT PRE-TREATMENT PET-CT POST-TREATMENT CARDAMON STUDY 4 X CCD

38. Case 5 Tom Discordance between: 1.Serological response Kappa FLC 4156  32 mg/L (VGPR) 2. Radiological response Ongoing disease which is FDG avid What do you do now?

39. Case 5: Tom Observe Further chemotherapy Consolidate with radiotherapy

40. Case 5 Tom Unclear what to do ? persistent disease and site of relapse in future ? delayed radiological response incorporate radiological and serological response Decision to give radiotherapy (site of bulk disease) CARDAMON study Treated as a VGPR (serological response criteria) Stem cell harvest Randomised to ASCT vs Consolidation therapy

41. Summary Whole body imaging routine practice in all patients with suspected or confirmed diagnosis of myeloma - bone disease or not ? What to do with patients with likely MGUS ? Choice of whole body imaging dependent on patient factors and local availability Assessment of response currently based on serology and clinical assessment Functional imaging will be used to assess response in future (currently research tool) Whole body imaging can be used to assess patients at relapse and decision on need for therapy

42. Acknowledgement Myeloma team at UCH Kwee Yong Atul Mehta Rakesh Popat Shirley D’Sa Ali Rismani Ashutosh Wechalekar Charalampia Kyriakou Plasma Cell Fellows + SpRs Myeloma CNSs Clinical Research Staff Radiology department at UCH/UCL Arash Latifoltojar Margaret Hall-Craggs Shonit Panwani